Results of Expert Meetings
Depression and ischemic heart disease: What have we learned so far and what must we do in the future?

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Depression: Risks for developing IHD

For centuries, poets and creators of folklore have asserted a relation between the mind and body, in particular, a physiological relation between emotional or psychological moods and the heart. Not until recent years, however, has this assertion been scientifically tested.

The earliest scientific test of the mind-body relation was conducted by Malzberg3 who published his results in 1937. He observed that patients with depression who had been chronically institutionalized had a mortality rate

Epidemiology of antidepressant therapy and the risk of cardiovascular disease

Identifying the mechanism or mechanisms by which depression might increase cardiovascular risk is a useful way to begin an analysis of observational studies that have investigated antidepressants and cardiovascular outcomes. Depression may heighten the risk of CVD by ā€œnonspecificā€ mechanisms such as its effect on the modulation of risk factors, particularly its tendency to weaken a patient's adherence to a program of risk factor modification. Depression might also increase the risk of CVD by

Polymorphisms of the serotonin transporter gene promoter region and depression

The poor prognosis observed in depressed patients with IHD may be mediated by increased sympathetic nervous system (SNS) or hypothalamic-pituitary-adrenal (HPA) axis functions. Veith et al,43 using 3H-norepinephrine dilution to index norepinephrine appearance, demonstrated that patients with depression have an increased SNS outflow. In other studies, treatments using both SSRI antidepressants and ā€œhostility reduction trainingā€ based on cognitive behavior therapy (CBT) have reduced SNS outflow

Heart rate variability and depression

Heart rate variability (HRV) is a well-accepted indicator of cardiac autonomic modulation. Low or decreased HRV suggests excessive sympathetic and/or inadequate parasympathetic activity, and it is a powerful independent predictor of mortality in patients with a recent MI,57, 58 stable IHD,59 or CHF.60 Depressed IHD patients have lower HRV than nondepressed IHD patients.61, 62, 63, 64, 65 We recently confirmed, in the largest study to date, that HRV is significantly lower in depressed than in

Inflammatory process, Omega-3, and depression

Subacute inflammation may play a significant role in IHD.68 For example, increased levels of C-reactive protein (CRP), interleukin 6, and soluble intercellular adhesion molecule have been found in the serum of patients with IHD. These inflammation markers have also been reported to mark atherosclerotic instability, to predict the incidence of IHD in previously healthy subjects, and to predict the prognosis of patients with established IHD.

A recent meta-analysis study of patients without IHD

Ventricular arrhythmia and depression

Following are some important facts to consider with regard to depression and ventricular arrhythmias in IHD:

  • 1.

    Depression increases the risk of IHD (unstable angina pectoris or MI).20

  • 2.

    The frequency and complexity of ventricular arrhythmias are increased in IHD, especially after MI.73

  • 3.

    Ventricular arrhythmias are not increased in patients who are depressed after MI.11

  • 4.

    Treatment of ventricular arrhythmias after MI with class I antiarrhythmic drugs (sodium-channel blockers) is associated with a

Platelet aggregation and depression

Increased platelet aggregation, which plays a significant role in coronary occlusion, is considered 1 of several potential biologic abnormalities associated with depression.80, 81, 82, 83 Musselman et al80 were the first investigators to demonstrate that platelet activation increased in patients with major depression. In their study, patients with major depression but no IHD proved to have 41% greater platelet activity than patients in the control groups. Among patients with IHD, those with

Randomized trials in post-MI patients with depression

Three large-scale studies were undertaken to examine the efficacy and safety of certain interventional modalities in post-MI patients with or without depression: MHART,88 ENRICHD),89 and SADHART.78 Their findings present a broad challenge to conventional beliefs in the combined fields of psychiatry and cardiology. The results require that we rethink our current understanding of the cardiovascular implications of depression and continue research efforts for understanding the complex effects of

What can we learn from the MHART and ENRICHD trials?

The ENRICHD trial failed to show a significant prognostic benefit among the post-MI patients randomized to cognitive-behavioral intervention compared with the usual-care group.89 As noted earlier, there were trends toward a negative treatment effect in female patients and a positive treatment effect in male patients. A similar finding among women in the MHART study forces us to consider the possibility that women may actually be harmed by cognitive-behavioral interventions like those used in

New science in old paradigms

Many things that investigators do in the course of conducting clinical trials for patients with depression tend to minimize treatment response, to enhance placebo response, and in studies of combination treatments, to inflate the value of active psychosocial comparisons. Several key factors contribute to the methodological limitations that can diminish the usefulness of these kinds of trials. It is important to examine these factors and ensure that they do not impair future studies in

Sex and ethnicity

It was not generally recognized until recently that male and female patients may have different responses to the same intervention and that this observation also holds true for patients from different ethnic backgrounds. Results from the MHART88 and ENRICHD89 trials showed sex-differentiated responses to the psychosocial therapy applied in the MHART trial and the CBT intervention applied in the ENRICHD study.

Before these trials were undertaken, psychosocial therapy had been presumed to have no

Depression and cardiovascular risk: Regional differences

In European countries, international differences in the risk for developing IHD have been well documented. The gradient for these differences appears in an east-west direction, as well as a north-south direction; a much higher incidence of IHD is found in the eastern and northern areas as compared with other parts of Europe. There is also regional variation in the incidence of depression. Although data are limited, Paykel and Priest110 summarized studies that reported very low incidence rates

Regulatory issues in clinical trials involving study sites in different countries

Several guidelines published in Europe focus on the international differences in treatment effects, medical practice styles, and research methodologies, each of which may affect both the conduct of and the data from multinational clinical trials. These are sometimes called ā€œumbrellaā€ guidelines.

  • 1.

    The International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)/E (Efficacy) 6, Notes for Guidance on Good Clinical Practice, 1996.111

  • 2.

Ethical issues related to informed consent for clinical trials that investigate the relation between depression and IHD

Clinical trials that investigate the relation between depression and IHD raise important ethical issues common to most clinical research. These ethical issues relate to aspects of trial design, such as selecting appropriate participants for the study and making appropriate decisions about the use of randomization and/or placebo controls, and to the clinical research process, such as attending to the best interests of the trial participants and conducting the research responsibly.115 In addition

Open discussion: Future trials

This conference confirmed that significant advances have been made over the last decade in our understanding of the consequences of concomitant depression and IHD. The epidemiological association between depression and poor outcomes in patients with CVD has been solidified, and there is consensus regarding the fact that specific interventions should be tested in clinical trials. Multiple dimensions are central to design decisions for these potential trials. Key dimensions of possible clinical

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